The way cancer-causing proteins accumulate in tumours may influence how effectively a promising new generation of medicines can remove them, a study suggests.
Category: biotech/medical – Page 62
Alzheimer’s Damage in Mice Reversed With Just Two Injections
Slowing the progression of Alzheimer’s disease is the goal of most existing treatments, but reversing it is much harder. That’s because once neurons are lost, the adult brain lacks the ability to replace them.
But new research, led by scientists at the University of South Carolina, has shown promise in regrowing neurons in brain organoids, and restoring cognition in mouse models of Alzheimer’s.
“After just two injections, these mice became smarter,” says Peisheng Xu, professor of pharmaceutics at the University of South Carolina and corresponding author of the new study, published in the journal Cell Biomaterials.
Athome urine test can detect nine in 10 cases of bladder cancer
Around 10,900 new bladder cancer cases are diagnosed every year in the UK
Nanoparticles regenerate neurons and improve cognition in Alzheimer’s mice
The adult human brain has limited capacity to repair or regenerate neurons lost to Alzheimer’s disease, the most common type of dementia. Existing treatments can slow disease progression but do not reverse cognitive decline. In a study publishing in the Cell Press journal Cell Biomaterials on August 26, researchers show that engineered nanoparticles can not only regenerate neurons in human brain organoids but also restore neural circuits and improve cognition in mice.
The new neurons can become mature and survive. We also confirmed much higher neuron density in the brains of treated mice.
Cell factories that manufacture microvesicles containing gene silencing RNA prodrugs
Precise and reversible suppression of gene expression by antisense RNA sequences is a strategy that is widely used in both basic research and clinical medicine (for reviews, see 1–3). Naked or unmodified antisense RNA is rapidly degraded in biological fluids and is inefficiently internalized by cells (4, 5). Consequently, antisense RNAs used to silence gene expression have been delivered by encapsulating them extracellularly in lipid-based or gold-based nanoparticles (6, 7) or in vesicles released from cells grown in culture (8–11). However, consistent and quantitatively reproducible RNA encapsulation in particles formed extracellularly has been a challenge (12, 13).
Arrestin domain–containing 1 (ARRDC1)-mediated microvesicles (ARMMs) are a naturally occurring distinct subclass of extracellular vesicles (EVs) that are uniquely dependent on the production of the arrestin-like cellular protein ARRDC1, and which—unlike other vesicles released from cells—are formed by outward budding of cytoplasmic membranes (14). During ARMMs formation, the ARRDC1 protein is attached to ARMMs membranes and is loaded into ARMMs—carrying along other macromolecules linked to it (14, 15). ARMMs can fuse with the plasma membranes of cells they encounter, and ARMMs cargos are discharged directly into the cytosol of recipient cells instead of being internalized by endocytosis—thus avoiding degradative actions of endosomal enzymes (14, 15). Collectively, these properties have prompted investigation of ARMMs’ abilities to deliver biologically manufactured macromolecules intercellularly (15–17).
Here, we describe and test a platform that synthesizes short hairpin RNA (shRNA) prodrugs as biochemically inert modules that are protected from RNA processing and degradation during their production and loading into ARMMs, but which become active gene-silencing agents upon delivery to recipient cells.
Robust inference and correlates from genetic associations with personality
Among participants with EUR-like genomes, SNP heritability (h2SNP) estimated for the Big Five traits using linkage disequilibrium score regression (LDSC)34 ranged from 4.8% (s.e. = 0.2%) for agreeableness to 9.3% (s.e. = 0.3%) for extraversion (Table 1, Supplementary Table 4 and Supplementary Note 3). Importantly, these SNP heritability estimates from GWAS meta-analysis index genetic effects that are consistent across contributing cohorts. To allow for variability in genetic effects across cohorts, we conducted a random effects meta-analysis of cohort-specific h2SNP estimates, which indicated an average h2SNP of 8.6% (s.e. = 0.6%) across traits (ranging from 7.4% for agreeableness to 10.6% for extraversion; Table 1 and Supplementary Table 21), with significant variability across cohorts (mean τ = 3.6%). Random response error by the participants cannot systematically relate to their genome35,36. Accordingly, we found that personality measures with greater reliability (lower random response error) tended to be more heritable (b = 6.7%, s.e. = 0.7%; Extended Data Fig. 2). In this analysis, the expected h2SNP for a measure of typical (median) reliability (α = 0.81) ranged from 9.3% for agreeableness (s.e. = 0.6%) to 13.3% for extraversion (s.e. = 0.6%), and h2SNP completely disattenuated for measurement error ranged from 10.8% for agreeableness (s.e. = 0.9%) to 15.8% for extraversion (s.e. = 0.9%; Table 1).
To further characterize the generalizability of genetic associations with personality, we examined the concordance of genetic signal across geography, age, veteran status, measurement instrument and reporter perspective (Table 1 and Extended Data Fig. 3). Genetic effects were similar but not identical across four western country clusters (USA, continental Europe, Nordic and UK–Australia, mean rg = 0.86, mean s.e. = 0.15), three age groups (young (≤25 years), middle (25–64 years) and older (65 years and older), mean rg = 0.80, mean s.e. = 0.18), between the Million Veteran Program and other, primarily non-veteran cohorts (mean rg = 0.82, mean s.e. = 0.04), and across five personality measurement instruments (mean rg = 0.85, mean s.e. = 0.07). Additional characterization of genetic architecture across measurement instruments using genomic structural equation modelling37 confirmed that genetic effects plausibly operate at the level of broad cross-instrument latent factors, with only one locus showing significantly heterogenous effects across measurement instruments (Supplementary Tables 22 – 24 and Extended Data Fig. 4). Notably, genetic associations with agreeableness were less consistent across cohorts (Table 1), explaining in part why agreeableness exhibited lower heritability than other traits in the meta-analytic GWAS. In the Estonian Biobank, in which the personality of the participants was assessed both by their self-report (n = 73,983) and by reports by close others (n = 20,269), we found strong genetic overlap between rater perspectives (mean rg = 0.84, mean s.e. = 0.12), indicating that the genetic architecture of personality is not an epiphenomenon of self-perception. In sex-stratified analyses of neuroticism in the UK Biobank cohort, X-chromosome-linked h2SNP did not differ between male individuals (n = 168,989; h2SNP, X = 0.23%; s.e. = 0.04%) and female individuals (n = 198,139; h2SNP, X = 0.18%; s.e. = 0.03%; Pdifference = 0.33). The dosage compensation ratio (\(\hat{{m{\gamma }}}\) = 1.26, s.e. = 0.30) was intermediate between no compensation (0.5) and full compensation (2.0) but was estimated relatively imprecisely. Genetic effects were correlated near-unity across sex (rg = 0.96; 95% confidence interval (CI) = 0.81–1.10).
Biological follow-up of GWAS signals indicated that enriched gene sets intersected across the Big Five (mean enrichment rank-order ρ = 0.72; Extended Data Fig. 5), providing evidence for trait-overlapping molecular and cellular systems in personality neurobiology despite only modest genetic correlations (Fig. 1f). Consistent with theories of personality development that emphasize the prefrontal cortex38,39, genetic associations for each Big Five trait, except for agreeableness, were enriched in genes expressed in the prefrontal cortex (among these, top lead SNPs implicate RCE1, FOXP2 and SEMA6D, indicated in Fig. 1; Supplementary Tables 25–34). All traits demonstrated strong enrichment in protein-truncating variant-intolerant gene sets specifically expressed in neurons (such as ARNTL, TCF4 and NEGR1; Fig. 1).
Less-intensive drug combination is more effective in treating acute myeloid leukemia, clinical trial finds
Investigators from the Mass General Brigham Cancer Institute have found that adults with newly diagnosed acute myeloid leukemia (AML) receiving a less-intensive combination of azacitidine and venetoclax had more than twice as much time before treatment failed, the leukemia returned or worsened, or they died, compared with patients receiving intensive chemotherapy. Published in the New England Journal of Medicine, the findings could change the initial treatment approach for many patients with AML.
“Less-intensive treatment does not necessarily mean less-effective treatment,” said lead author Amir T. Fathi, MD, director of the Leukemia Program at the Mass General Brigham Cancer Institute. “Our goal is to optimally treat acute myeloid leukemia while reducing serious complications and the amount of time patients spend in the hospital.”
The less-intensive combination is already used in older patients or those unable to tolerate intensive chemotherapy. The PARADIGM trial tested whether it could work as well—or better—for patients who could receive intensive chemotherapy, including younger patients.
When we eat helps set the liver’s metabolic rhythms
When we think about metabolism, we usually ask, “What did I eat? How much sugar, fat or protein was in the meal?” But through our research, we have become interested in another question: “When did I eat it?” This matters because metabolism does not work at the same pace throughout the day.
The liver, one of our main metabolic organs, follows daily rhythms that help coordinate how nutrients are processed, stored and used. These rhythms are controlled partly by the molecular circadian clock, present in virtually all body cells, but eating also provides an important signal.
In our recent study published in Cell Reports, we set out to understand how the timing of food intake influences these daily metabolic rhythms. What we found points to a mitochondrial enzyme, ACSF3, as a potential link between feeding time and the temporal organization of liver metabolism.
Immunotherapy before brain tumor surgery shows surprising benefits
Early CAR-T treatment shows surprising results in brain tumors.
Breakthrough Helps Expand Genetic Alphabet
All known life on earth utilizes the same genetic alphabet, consisting of four letters. Now, researchers at University of California San Diego have demonstrated that one of biology’s most essential enzymes can accurately read and transcribe an expanded, eight-letter genetic alphabet. The findings provide important evidence that cells can process synthetic genetic information using their natural molecular machinery, advancing a long-standing goal in synthetic biology to expand the language of DNA. It could also allow scientists to custom-engineer biological systems that perform functions or produce compounds not found in nature.
The study focused on RNA polymerase, the enzyme responsible for reading DNA and producing RNA — the first step in gene expression. Using biochemical experiments and high-resolution cryo-electron microscopy that can zoom down to smaller than the width of a single atom, researchers captured detailed structural snapshots showing how RNA polymerase from Escherichia coli ( E. coli ) bacteria recognizes and incorporates two synthetic base pairs, genetic letters that are not found in nature. These snapshots revealed that the enzyme recognizes synthetic DNA letters through the same biochemical and structural signals as natural base pairs, helping explain how expanded genetic information can be faithfully transcribed. In another related study, the same researchers reported that RNA polymerase can also recognize another pair of synthetic base pairs without hydrogen bonds to hold them together, published in PNAS.
This work has implications beyond basic biology. Previous studies have used expanded genetic alphabets to create synthetic DNA molecules capable of recognizing liver cancer cells. By revealing how RNA polymerase accurately reads and transcribes these non-natural DNA letters, the new study provides a molecular foundation for future technologies that use expanded genetic codes, including new diagnostics, therapeutics and engineered biological systems.